Current regulatory practices for chemical carcinogens were established when scientific understanding of the molecular mechanisms of chemical carcinogenesis was in its infancy. Initial discovery that DNA mutation was the root of cancer led quickly to regulatory processes that assumed such a simple relationship could be described with a linear approach. This linear, no threshold approach has since become the default approach to risk assessment of chemicals with carcinogenic potential. Since then, a multitude of intrinsic processes have been identified at the molecular, cellular and organism level that work to prevent transient DNA damage from causing permanent mutations, and mutated cells from becoming cancer. Mounting evidence indicates that these protective mechanisms can prevent carcinogenesis at low doses of genotoxic chemicals, leading to non-linear dose-response. Further, a number of non-genotoxic mechanisms have demonstrated threshold-shaped dose-response for cancer outcomes. The existence of non-linear dose-response curves for both non-genotoxic and genotoxic chemical carcinogens stands in stark contrast to the default risk assessment approach that assumes low dose linearity. In this review, we highlight some of the key discoveries and technological advances that have influenced scientific understanding of chemical carcinogenesis over the last fifty years and provide case studies to demonstrate the utility of these modern technologies in providing a biologically robust evaluation of chemical dose-response for cancer risk assessment.